Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a foxed double transgenic model of Alzheimer's disease

Synapse number is the best indicator of cognitive impairment In Alzheimer's disease (AD), yet the respective contributions of A beta and tau, particularly human wild-type tau, to synapse loss remain undefined. Here, we sought to elucidate the A beta-dependent changes in wild-type human tau that trigger synapse loss and cognitive decline in AD by generating two novel transgenic mouse models. The first overexpresses foxed human APP with Swedish and London mutations under the thyl promoter, and recapitulates important features of early AD, including accumulation of soluble A beta and oligomers, but no plaque formation. Transgene excision via Cre-recombinase reverses cognitive decline, even at 18-months of age. Secondly, we generated a human wild-type tauoverexpressing mouse. Crossing of the two animals accelerates cognitive impairment, causes enhanced accumulation and aggregation of tau, and results in reduction of dendritic spines compared to single transgenic hTau or hAPP mice. These results suggest that A beta-dependent acceleration of wild-type human tau pathology is a critical component of the lasting changes to dendritic spines and cognitive impairment found in AD. (c) 2014 Elsevier Inc. All rights reserved.